Glycoprotein nonmetastatic melanoma protein B ameliorates skeletal muscle lesions in a SOD1^G93A mouse model of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons and subsequent muscular atrophy. The quality of life of patients with ALS is significantly improved by ameliorating muscular symptoms. We previously reported that glycoprotein nonmetastatic melanoma protein B (GPNMB; osteoactivin) might serve as a target for ALS therapy. In the present study, superoxide dismutase 1/glycine residue 93 changed to alanine (SOD1(G93A) ) transgenic mice were used as a model of ALS. Expression of the C-terminal fragment of GPNMB was increased in the skeletal muscles of SOD1(G93A) mice and patients with sporadic ALS. SOD1(G93A) /GPNMB transgenic mice were generated to determine whether GPNMB expression ameliorates muscular symptoms. The weight and cross-sectional area of the gastrocnemius muscle, number and cross-sectional area of myofibers, and denervation of neuromuscular junctions were ameliorated in SOD1(G93A) /GPNMB vs. SOD1(G93A) mice. Furthermore, direct injection of a GPNMB expression plasmid into the gastrocnemius muscle of SOD1(G93A) mice increased the numbers of myofibers and prevented myofiber atrophy. These findings suggest that GPNMB directly affects skeletal muscle and prevents muscular pathology in SOD1(G93A) mice and may therefore serve as a target for therapy of ALS.

GPNMB ameliorates mutant TDP‐43‐induced motor neuron cell death

“…Glycosylated GPNMB is the mature isoform of GPNMB (Hoashi et al, ), and two isoform of glycosylated GPNMB was reported which molecular weights of 90 and 100 kDa (Furochi et al, ; Singh et al, ). In this study, we quantified the expression of total glycosylated GPNMB (sum of 90 kDa and 100 kDa), the same as our previous report (Nagahara et al, ).…”

“…Although overexpression of mutant SOD1 is one of the most widely used ALS models, ALS caused by mutant SOD1 accounts for only about 20% of familial ALS (Dion et al, ). Our previous results indicate that GPNMB may be a therapeutic target against ALS associated with SOD1 (G93A) (Nagahara et al, ; Nagahara et al, ; Tanaka et al, ). However, it is unclear whether GPNMB has protective effects against ALS independent of SOD1 mutation.…”

“…Furthermore, GPNMB prevented motor neuron cell death induced by overexpression of SOD1 (G93A), and GPNMB prolonged the survival rate of mice in the SOD1 (G93A) model of ALS (Tanaka et al, ). GPNMB also ameliorates skeletal muscle lesions in a SOD1 (G93A) mice (Nagahara et al, ; Nagahara et al, ). GPNMB is deposited extracellularly in the lumbar spinal cord of ALS patients (Tanaka et al, ).…”

The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis

“…Delivery approaches included the use of retroviral vectors (69,80,124), electroporation (132), transgenic muscle-restricted overexpression (67) and intramuscular transplantation of stem cells (61, 91,111). Neuroprotective effects were also obtained by delivering other neurotrophic factors, such as Ù myofiber number Ú myofiber atrophy (83) " …”

Adverse left ventricular remodeling by glycoprotein nonmetastatic melanoma protein B in myocardial infarction

“…GPNMB plays a role in extracellular matrix (ECM) remodeling in osteoblast and fibroblast differentiation and in increasing cancer metastasis by induction of matrix metalloproteinases (MMP)3 and MMP9 (3,(7)(8)(9)(10). Importantly, GPNMB promotes regeneration after muscle, kidney, liver, and cerebral ischemiareperfusion injury by regulation of immune/inflammatory responses and suppressing fibrosis (11)(12)(13)(14). However, the functions of GPNMB in pathophysiological processes in the heart are still unknown, although GPNMB was recently mentioned in a screen of viral cardiomyopathy (15).…”